The present patent application relates to new compounds of general formula 1 
wherein the groups A, X, R1, R2, R3, R4, R5, and R6 have the meanings given in the specification and claims, processes for preparing them, and their use as pharmaceutical compositions, particularly as pharmaceutical compositions for the prevention or treatment of diseases the cause of which is based on a functional disorder caused by overstimulation.
The aim of the present invention is to prepare new compounds which can be used as blockers of the voltage-dependent sodium channel. Compounds of this kind can be used to treat diseases which are caused by a functional disorder resulting from overstimulation. These include diseases such as arrhythmias, spasms, cardiac and cerebral ischemias, pain, and neurodegenerative diseases of various origins. These include, for example: epilepsy, hypoglycemia, hypoxia, anoxia, brain trauma, brain edema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotrophic lateral sclerosis, Huntington""s disease, Alzheimer""s disease, Parkinson""s disease, cyclophrenia, hypotonia, cardiac infarction, heart rhythm disorders, angina pectoris, chronic pain, neuropathic pain, and local anesthesia.
The problem stated above is solved by the compounds of general formula 1 disclosed in the description which follows.
The present patent application relates to new compounds of general formula 1 
wherein:
R1 denotes hydrogen, hydroxy, CF3, NO2, CN, halogen, C1-C8-alkyl, or C1-C8-alkoxy;
R2, R3, and R4 independently of one another denote hydrogen, C1-C8-alkyl, hydroxy, NO2, CN, C1-C8-alkyloxy, CF3, or halogen;
R5 and R6 independently of one another denote hydrogen or a group selected from among C1-C8-alkyl, C2-C8-alkenyl, C3-C8-alkynyl, C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C6-alkylene, C5-C8-cycloalkenyl, C5-C8-cycloalkenyl-C1-C6-alkylene, C6-C10-aryl, and C6-C10-aryl-C1-C6-alkylene, which may optionally be substituted by a group selected from among C1-C6-alkyl, C2-C6-alkenyl, halogen, C1-C6-alkyloxy, xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, hydroxy, xe2x95x90O, xe2x80x94COOH, xe2x80x94COxe2x80x94OC1-C4-alkyl, xe2x80x94CONH2, xe2x80x94CONH(C1-C4-alkyl), xe2x80x94CON(C1-C4-alkyl)2, and CF3, or
R5 and R6 together with the nitrogen atom denote a saturated or unsaturated 5-, 6-, 7-, or 8-membered heterocyclic group which optionally contains one or two further heteroatoms selected from sulfur, oxygen, and nitrogen and may optionally be mono-, di-, or trisubstituted by a group selected from C1-C4-alkyl, hydroxy, xe2x95x90O, xe2x80x94COOH, xe2x80x94COxe2x80x94OC1-C4-alkyl, xe2x80x94CONH2, xe2x80x94CONH(C1-C4-alkyl), xe2x80x94CON(C1-C4-alkyl)2, halogen, and benzyl;
X denotes oxygen, xe2x80x94NHxe2x80x94, xe2x80x94N(CHO)xe2x80x94, xe2x80x94N(COxe2x80x94C1-C6-alkyl), xe2x80x94N(C1-C6-alkyl), or xe2x80x94N(C3-C6-cycloalkyl-C1-C4-alkylene), preferably oxygen or xe2x80x94NHxe2x80x94;
A denotes a group selected from C1-C6-alkylene, C2-C6-alkenylene, and C3-C6-alkynylene, which may optionally be substituted by a group selected from halogen, xe2x95x90O, and hydroxy.
Preferred compounds of general formula 1 are those wherein
R1 denotes hydrogen, halogen, C1-C6-alkyl, CF3, or methoxy;
R2, R3, and R4 independently of one another denote hydrogen, C1-C6-alkyl, C1-C6-alkyloxy, CF3, or halogen;
R5 and R6 independently of one another denote hydrogen or a group selected from among C1-C6-alkyl, C2-C6-alkenyl, C3-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C6-alkylene, C5-C6-cycloalkenyl, C5-C6-cycloalkenyl-C1-C6-alkylene, phenyl, and phenyl-C1-C6-alkylene, which may optionally be substituted by a group selected from among C1-C4-alkyl, C2-C4-alkenyl, halogen, C1-C4-alkyloxy, hydroxy, xe2x80x94CONH2, xe2x95x90O, and CF3, or
R5 and R6 together with the nitrogen atom denote a saturated or unsaturated 5-, 6-, or 7-membered heterocyclic group which optionally contains one or two further heteroatoms selected from sulfur, oxygen, and nitrogen and may optionally be mono-, di-, or trisubstituted by C1-C4-alkyl, xe2x80x94CONH2, or hydroxy;
X denotes oxygen, xe2x80x94NHxe2x80x94, xe2x80x94N(CHO)xe2x80x94, xe2x80x94N(COxe2x80x94C1-C5-alkyl), xe2x80x94N(C1-C5-alkyl), or xe2x80x94N(C3-C6-cycloalkyl-C1-C4-alkylene), preferably oxygen or xe2x80x94NHxe2x80x94; and
A denotes C1-C5-alkylene, C2-C4-alkenylene, or C3-C4-alkynylene, preferably C1-C5-alkylene.
Particularly preferred are compounds of general formula 1, wherein
R1 denotes hydrogen, C1-C4-alkyl, or CF3;
R2, R3, and R4 independently of one another denote hydrogen, C1-C4-alkyl, CF3, or halogen;
R5 and R6 independently of one another denote hydrogen, C1-C6-alkyl, CF3xe2x80x94C1-C6-alkylene, preferably selected from xe2x80x94CH2xe2x80x94CF3, xe2x80x94CH2xe2x80x94CH2xe2x80x94CF3, C2-C6-alkenyl, C3-CC6-alkynyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C6-alkylene, preferably cyclopropylmethyl or cyclohexenemethyl, cyclohexenyl, cyclohexenyl-C1-C6-alkylene, propenyl-cyclohexenylene-C1-C6-alkylene, phenyl, or phenyl-C1-C6-alkylene, or
R5 and R6 together with the nitrogen atom denote a saturated or unsaturated 5-, 6-, or 7-membered heterocyclic group, which optionally contains another nitrogen atom and may optionally be mono-, di-, or trisubstituted by C1-C4-alkyl, xe2x80x94CONH2, or hydroxy;
X denotes oxygen, xe2x80x94NHxe2x80x94, xe2x80x94N(CHO)xe2x80x94, xe2x80x94N(CO-methyl), xe2x80x94N(CO-ethyl), xe2x80x94N(C1-C5-alkyl), or xe2x80x94N(C3-C6-cycloalkyl-methylene), preferably oxygen or xe2x80x94NHxe2x80x94; and
A denotes xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94.
Also particularly preferred are compounds of general formula 1, wherein:
R1 denotes hydrogen or methyl;
R2 and R3 independently of one another denote hydrogen, methyl, fluorine, chlorine, or bromine;
R4 denotes hydrogen, fluorine, chlorine, or bromine;
R5 and R6 independently of one another denote hydrogen, C1-C6-alkyl, CF3-C1-C6-alkylene, preferably xe2x80x94CH2xe2x80x94CH2xe2x80x94CF3, C2-C6-alkenyl, butenyl, pentenyl, C3-C6-cycloalkyl, preferably cyclohexyl, C3-C6-cycloalkyl-C1-C6-alkylene, cyclopropylmethyl, or cyclohexenemethyl, cyclohexenyl, cyclohexenyl-C1-C6-alkylene, preferably cyclohexenyl-CH2xe2x80x94, or
R5 and R6 together with the nitrogen atom denote a heterocyclic group selected from among pyrrolidine, piperidine, 1,2,3,6-tetrahydropyridine, and azepan;
X denotes oxygen, xe2x80x94NHxe2x80x94, xe2x80x94N(CHO)xe2x80x94, xe2x80x94N(CO-methyl), xe2x80x94N(CO-ethyl), xe2x80x94N(methyl)-, xe2x80x94N(ethyl)-, xe2x80x94N(propyl)-, xe2x80x94N(butyl)-, xe2x80x94N(pentyl)-, or xe2x80x94N(cyclopropylmethylene)-, preferably oxygen or xe2x80x94NHxe2x80x94; and
A denotes xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94.
Of particular importance according to the invention are compounds of general formula 1, wherein
R1 denotes hydrogen or methyl;
R2 and R3 independently of one another denote hydrogen, methyl, fluorine, chlorine, or bromine;
R4 denotes hydrogen, fluorine, chlorine, or bromine;
R5 and R6 independently of one another denote hydrogen, methyl, propyl, butyl, hexyl, cyclopropylmethyl, or cyclohexenemethyl, or
R5 and R6 together with the nitrogen atom denote a heterocyclic group selected from among pyrrolidine, piperidine, 1,2,3,6-tetrahydropyridine, and azepan;
X denotes oxygen, xe2x80x94NHxe2x80x94, xe2x80x94N(CHO)xe2x80x94, xe2x80x94N(CO-methyl), xe2x80x94N(CO-ethyl), xe2x80x94N(ethyl)-, xe2x80x94N(propyl)-, xe2x80x94N(butyl)-, xe2x80x94N(pentyl)-, or xe2x80x94N(cyclopropylmethylene)-, preferably oxygen or xe2x80x94NHxe2x80x94; and
A denotes xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94.
Of outstanding importance according to the invention are compounds of general formula 1, wherein
R1 denotes hydrogen or methyl;
R2 and R3 independently of one another denote hydrogen or fluorine;
R4 denotes hydrogen;
R5 and R6 independently of one another denote hydrogen, butyl, hexyl, or cyclohexenemethyl, or
R5 and R6 together with the nitrogen atom denote piperidine and 1,2,3,6-tetrahydropyridine;
X denotes oxygen or xe2x80x94NHxe2x80x94; and
A denotes xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94.
Compounds of general formula 1, wherein R1 denotes hydrogen, R2 and R3 are in the ortho position, and X, A, R2, R3, R4, R5, and R6 may have the meanings given hereinbefore, correspond to general formula 1xe2x80x2. 
These compounds are particularly important according to the invention.
Compounds of general formula 1, wherein R1 denotes methyl and is in the para position, R2 and R3 are in the ortho position, and X, A, R2, R3, R4, R5, and R6 may have the meanings given hereinbefore, correspond to general formula 1xe2x80x3. 
These compounds are particularly important according to the invention. Of special importance are the compounds of general formulae 1, 1xe2x80x2, and 1xe2x80x3, wherein R4 denotes hydrogen.
The invention relates to the compounds of formula 1 in question, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and in the form of the free bases or the corresponding acid addition salts thereof with pharmacologically acceptable acids, such as, for example, acid addition salts with hydrohalic acids, e.g., hydrochloric or hydrobromic acid, or organic acids, such as, e.g., oxalic, fumaric, or diglycolic acid, or methanesulfonic acid.
The present invention also relates to quaternary ammonium compounds such as may be formed from the compounds of formula 1 with alkyl halides of formula R7xe2x80x94X. Accordingly, the quaternary ammonium compounds of formula 1-Y are also important according to the invention: 
wherein the groups A, X, R1, R2, R3, and R4 may have the meanings given hereinbefore, R5 and R6 may have the meanings given hereinbefore with the exception of hydrogen, R7 denotes C1-4-alkyl, preferably methyl or ethyl, and Y denotes a halide selected from among chlorine, bromine, and iodine.
Compounds of general formula 1-Y, wherein R1 denotes hydrogen, R2 and R3 are in the ortho position, and X, A, R2, R3, R4, R5, R6, and R7 may have the meanings given hereinbefore, correspond to general formula 1xe2x80x2-Y. 
These compounds are particularly important according to the invention.
Compounds of general formula 1-Y, wherein R1 denotes methyl and is in the para position, R2 and R3 are in the ortho position, and X, A, R2, R3, R4, R5, and R6 may have the meanings given hereinbefore, correspond to general formula 1xe2x80x3-Y. 
These compounds are also important according to the invention. Of special importance are the compounds of general formulae 1-Y, 1xe2x80x2-Y, and 1xe2x80x3-Y, wherein R4 denotes hydrogen.
Of particular interest according to the invention are the following compounds:
(a) N-[2-[3-(2,6-difluorophenyl)propoxy]-2-(2,6-dimethylphenyl)ethyl]-N-n-butylamine;
(b) N-[[2-[3-(2,6-difluorophenyl)propoxy]-2-(2,6-dimethylphenyl)ethyl]-N-(2-ethylbutyl)-N,N-dimethylammonium iodide;
(c) 1-[2-[3-(2,6-difluorophenyl)propoxy]-2-(2,6-dimethylphenyl)ethyl]pyrrolidine;
(d) N-[2-[3-(2,6-difluorophenyl)propoxy]-2-(2,6-dimethylphenyl)ethyl]-N-(4-penten-1-yl)amine;
(e) N-[2-[3-(2,6-difluorophenyl)propoxy]-2-(2,6-dimethylphenyl)ethyl]-N-n-propylamine;
(f) N-[2-[3-(2,6-difluorophenyl)propoxy]-2-(2,4,6-trimethylphenyl)ethyl]-N,N-dimethylamine;
(g) 1-[2-[3-(2,6-difluorophenyl)propoxy]-2-(2,6-dimethylphenyl)ethyl]piperidine;
(h) N-[2-[3-(2,6-difluorophenyl)propoxy]-2-(2,6-dimethylphenyl)ethyl]-N-n-butyl-N,N-dimethylammonium iodide; and
(i) N-[2-[3-(2,6-difluorophenyl)propoxy]-2-(2,6-dimethylphenyl)ethyl]-N-(1-cyclohexen-4-ylmethyl)-N,N-dimethylammonium iodide.
Unless otherwise stated, the general definitions are used as follows:
The term alkyl groups (including those which are part of other groups) denotes branched and unbranched alkyl groups with 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, most preferably 1 to 4 carbon atoms, which may optionally be substituted by one or more halogen atom(s), preferably fluorine. The following hydrocarbon groups are mentioned by way of example: methyl, ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, and 1-ethyl-2-methylpropyl. Unless otherwise stated, lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, or 1,1-dimethylethyl are preferred. The definitions propyl, butyl, pentyl, etc., always include the associated isomeric groups. In some cases the common abbreviations are used for the abovementioned alkyl groups, such as Me for methyl, Et for ethyl, Prop for propyl, But for butyl, etc.
The term alkylene groups denotes branched and unbranched alkylene bridges with 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. The following are mentioned, for example: methylene, ethylene, propylene, butylene, etc. Unless otherwise stated, the terms propylene, butylene, etc., used above also include all the possible isomeric forms. Accordingly, the term propylene includes the isomeric bridges n-propylene, methylethylene, and dimethylmethylene and the term butylene includes the isomeric bridges n-butylene, 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene, and 1,2-dimethylethylene.
Cycloalkyl generally denotes a saturated cyclic hydrocarbon group with 3 to 8 carbon atoms, which may optionally be substituted by a halogen atom or several halogen atoms, preferably fluorine, which may be identical to or different from one another. Cyclic hydrocarbons with 3 to 6 carbon atoms are preferred. Examples of these include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
Alkenyl generally denotes a branched or unbranched hydrocarbon group with 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, most preferably 2 to 4 carbon atoms, which may have one or more double bonds and may optionally be substituted by one or more halogen atoms, preferably fluorine, while the halogens may be identical to or different from one another. The following alkenyl groups are mentioned by way of example: vinyl, 2-propenyl (allyl), 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl 3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, and 1-ethyl-2-methyl-2-propenyl, etc.
Cycloalkenyl generally denotes a cyclic hydrocarbon group with 5 to 8 carbon atoms, which contains at least one double bond and may optionally be substituted by one halogen atom or several halogen atoms, preferably fluorine, which may be identical to or different from one another. Generally, cyclopentenyl or cyclohexenyl are preferred, and unless otherwise stated these groups may be substituted by C1-C4-alkyl or C2-C4-alkenyl.
Alkynyl generally denotes a branched or unbranched hydrocarbon group with 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms, most preferably 3 to 5 carbon atoms, which may contain one or more triple bonds and may optionally be substituted by one or more halogen atoms, preferably fluorine, while the halogens may be identical to or different from one another. The following alkynyl groups are mentioned by way of example: ethynyl, 2-propynyl (propargyl), 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 2-methyl-2-butynyl, 3-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1,2-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-methyl-2-pentynyl, 4-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 3-methyl-3-pentynyl, 4-methyl-3-pentynyl, 1-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-4-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-2-butynyl, 1,2-dimethyl-3-butynyl, 1,3-dimethyl-2-butynyl, 1,3-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-1-butynyl, 2-ethyl-2-butynyl, 2-ethyl-3-butynyl, 1,1,2-trimethyl-2-propynyl, and 1-ethyl-1-methyl-2-propynyl.
Alkyloxy, which may also optionally be referred to as alkoxy, generally denotes a straight-chain or branched hydrocarbon group with 1 to 6 carbon atoms linked via an oxygen atom; a lower alkoxy group with 1 to 4 carbon atoms is preferred. The methoxy group is particularly preferred.
The term aryl denotes an aromatic ring system with 6 to 10 carbon atoms. Unless otherwise stated, the preferred aryl group is phenyl.
By cycloalkyl-alkylene is meant, for the purposes of the invention, cycloalkyl groups linked via an alkylene bridge. By cycloalkenyl-alkylene is meant, for the purposes of the invention, cycloalkenyl groups linked via an alkylene bridge. By aryl-alkylene is meant, for the purposes of the invention, aryl groups linked via an alkylene bridge.
The following are mentioned as examples of N-linked 5-, 6-, 7-, or 8-membered, saturated or unsaturated heterocyclic groups which may be formed by the groups R5 and R6 together with the nitrogen atom: pyrrole, pyrroline, pyrrolidine, 1,2,3,6-tetrahydropyridine, piperidine, piperazine, morpholine, thiomorpholine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, azepan, azepine, diazepine, etc., preferably pyrrolidine, piperidine, 1,2,3,6-tetrahydropyridine, and azepan.
The compounds claimed are blockers of the voltage-dependent sodium channel. These are compounds which displace batrachotoxin (BTX) with a high affinity (Ki less than 1000 nM) competitively or non-competitively from the binding site on the sodium channel. Such substances exhibit xe2x80x9cuse-dependencyxe2x80x9d in the blocking of the sodium channels, i.e., in order to bind the substances at the sodium channel, the sodium channels first have to be activated. Maximum blockage of the sodium channels is only achieved after repeated stimulation of the sodium channels. Consequently, the substances bind preferentially to sodium channels which are activated a number of times. As a result, the substances are in a position to become effective particularly in those parts of the body which are pathologically overstimulated. The compounds of general formula 1 according to the invention can thus be used to treat diseases which are caused by a functional disorder resulting from overstimulation. These include diseases such as arrhythmias, spasms, cardiac and cerebral ischemias, pain, and neurodegenerative diseases of various origins. These include, for example: epilepsy, hypoglycemia, hypoxia, anoxia, brain trauma, brain edema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotrophic lateral sclerosis, Huntington""s disease, Alzheimer""s disease, Parkinson""s disease, cyclophrenia, hypotonia, cardiac infarction, heart rhythm disorders, angina pectoris, chronic pain, neuropathic pain, and local anesthesia.
The blocking action on the sodium channel may be demonstrated by the test system which tests the BTX binding to the sodium channel [S. W. Postma and W. A. Catterall, Mol. Pharmacol 25, 219-227 (1984)] as well as by patch-clamp experiments which show that the compounds according to the invention block the electrically stimulated sodium channel in a xe2x80x9cuse-dependentxe2x80x9d manner [W. A. Catterall, Trends Pharmacol. Sci., 8, 57-65 (1987)]. By a suitable choice of cell system (e.g., neuronal, cardiac, DRG cells) it is possible to test the effect of the substances on different subtypes of sodium channel.
The sodium channel blocking property of the compounds according to the invention can be demonstrated by the blocking of the veratridine-induced release of glutamate [S. Villanueva, P. Frenz, Y. Dragnic, and F. Orrego, Brain Res. 461, 377-380 (1988)]. Veratridine is a toxin which opens the sodium channel permanently. This leads to an increased influx of sodium ions into the cell. By means of the cascade described above, this sodium influx leads to an increased release of glutamate in the neuronal tissue. The compounds according to the invention antagonize this release of glutamate.
The anticonvulsant properties of the substances according to the invention were demonstrated by their protective effect against convulsions triggered by a maximum electric shock in mice [M. A. Rogawski and R. J. Porter, Pharmacol. Rev. 42, 223-286 (1990)].
Neuroprotective properties were demonstrated by a protective effect in a rat MCAO model [U. Pschorn and A. J. Carter, J. Stroke, Cerebrovascular Diseases, 6, 93-99 (1996)] and a malonate-induced lesion model [M. F. Beal, Annals of Neurology, 38, 357-366 (1995) and J. B. Schulz, R. T. Matthews, D. R. Henshaw, and M. F. Beal, Neuroscience, 71, 1043-1048 (1996)].
Analgesic effects can be investigated in models of diabetic neuropathy and in a ligature model [C. Courteix, M. Bardin, C. Chantelauze, J. Lavarenne, and A. Eschalier, Pain 57, 153-160 (1994); C. Courteix, A. Eschalier, and J. Lavarenne, Pain 53, 81-88 (1993); G. J. Bennett and Y.-K. Xie, Pain 33, 87-107 (1988)].
It has also been reported that sodium channel blockers can be used to treat cyclophrenia (manic depressive disorder) [J. R. Calabrese, C. Bowden, M. J. Woyshville; in: Psychopharmacology: The Fourth Generation of Progress (Eds.: D. E. Bloom and D. J. Kupfer) 1099-1111 (New York: Raven Press Ltd.)].
The claimed compounds 1 can be prepared using methods known from the prior art. Some methods of synthesis will now be described by way of example.
Starting from the benzaldehyde derivatives of formula 2 it is possible to obtain the compounds of general formula 6 (corresponding to compounds of formula 1 wherein X denotes O and the groups R5 and R6 denote hydrogen), using the procedure illustrated in Diagram 1. 
Diagram 1
Starting from the 2,6-dimethylbenzaldehyde derivatives 2 according to step (i) the 2-amino-ethanols 3 are obtained by first taking up 2 in trimethylsilylcyanide in the presence of a Lewis acid, preferably in the presence of zinc iodide. After the abovementioned reactants have been mixed together, preferably at ambient temperature, the mixture is diluted with an anhydrous organic solvent, preferably with an ethereal organic solvent, most preferably with diethylether, tetrahydrofuran, or dioxane. Then a reducing agent is added, preferably a metal hydride, most preferably a hydride selected from lithium aluminium hydride or sodium-bis(2-methoxyethoxy)aluminium hydride (Red-A1(copyright)). To complete the reaction, the mixture is stirred at elevated temperature, most preferably at the reflux temperature of the solvent used, for 0.5 to 4, preferably 2 hours. The reaction mixture is worked up in the usual way. The products are purified by crystallization or by chromatographic methods depending on their crystallization tendencies.
At the aminoalcohol stage 3 the racemate may optionally be separated into the enantiomers. The subsequent separation of the mixture of the enantiomeric aminoalcohols of type 3 thus obtained may be carried out using the methods of enantiomer separation known from the prior art, e.g., by reacting with malic acid, tartaric acid, mandelic acid, or camphorsulfonic acid, of which tartaric acid is particularly preferred.
The trifluoroacetates 4 (stage 3 (ii)) are prepared as follows from the compounds 3 optionally thus obtained in enantiomerically pure form. The alcohols 3 are dissolved in an organic solvent, preferably in an anhydrous organic solvent, most preferably in a solvent selected from among toluene, ether, dichloromethane, DMF, and ethyl acetate, and trifluoroacetic anhydride is added in the presence of an organic or inorganic base at ambient temperature or while cooling with ice, and the resulting mixture is stirred for 1 to 8 hours, preferably 2 to 6 hours, most preferably about 4 hours. The inorganic base used may be an alkali metal- or alkaline earth metal carbonate of lithium, sodium, potassium, or calcium, such as, sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, and preferably potassium carbonate. The organic base is preferably an organic amine, most preferably diisopropylethylamine, triethylamine, a cyclic amine such as DBU, or pyridine. The abovementioned amines may optionally also be used as solvents. The reaction mixture is worked up in the usual way. The products are purified by crystallization or by chromatographic methods depending on their crystallization tendencies.
In order to prepare the compounds of formula 6 (corresponding to compounds of formula 1 wherein X denotes O and the groups R5 and R6 denote hydrogen) a compound 4 according to stage (iii) is dissolved in an organic solvent, preferably in an anhydrous organic solvent, most preferably in a solvent selected from among toluene, ether, dichloromethane, DMF, and ethyl acetate and combined with a compound of formula 5, optionally dissolved in one of the abovementioned organic solvents, in the presence of an organic base, preferably selected from diisopropyl ethylamine, triethylamine, cyclic amines such as DBU, and pyridine, at ambient temperature or in the presence of an inorganic base, preferably in the presence of alkali or alkaline earth metal carbonates of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, or in the presence of the alkali metal hydrides or alkaline earth metal hydrides such as sodium hydride, calcium hydride, or potassium hydride, or in the presence of the alkali metal alkoxides, preferably potassium tert-butoxide, sodium methoxide, or sodium ethoxide, at ambient temperature or preferably at temperatures between xe2x88x9220xc2x0 C. and ambient temperature, most preferably at about 0xc2x0 C. When sodium hydride is used as the base, it may be helpful to use chelating agents such as crown ethers, preferably 15-crown-5. To complete the reaction the mixture is stirred at ambient temperature or at elevated temperature, preferably at the boiling temperature of the solvent used, for 2 to 24 hours, preferably 4 to 12 hours, most preferably 6 to 7 hours. The reaction mixture is worked up in the usual way. The products are purified by crystallization or by chromatographic methods depending on their crystallization tendencies.
An alternative method of obtaining compounds of general formula 6 (corresponding to 1 wherein X denotes oxygen and R5 and R6 denote hydrogen), starting from the benzaldehyde derivatives of formula 2, is the procedure illustrated in Diagram 2. 
Diagram 2
Starting from the 2,6-dimethylbenzaldehyde derivatives (2) according to stage (iv) the reaction to obtain the xcex1,xcex2-unsaturated nitro compounds 7 is carried out using nitromethane in glacial acetic acid at elevated temperature, preferably at above 60xc2x0 C., most preferably above 100xc2x0 C., preferably at about 120xc2x0 C. over a period of 2 to 8, preferably 3 to 6, most preferably about 4 hours. The reaction mixture is worked up in the usual way. The products are purified by crystallization or by chromatographic methods depending on their crystallization tendencies.
The ethers 9 may be obtained from the nitro compounds 7 by reacting with the alcohols 8. This is done as follows. The alcohol 8 is dissolved in an organic solvent, preferably in an anhydrous organic solvent selected from among methylene chloride, tetrahydrofuran, diethylether, and dioxane, and combined with a base selected from the alkali metal alkoxides such as sodium ethoxide, sodium methoxide, or potassium tert-butoxide, and the alkali metal- or alkaline earth metal hydrides, preferably sodium hydride. The mixture is stirred for 6 to 24, preferably about 10 to 14 hours at ambient temperature, optionally also at slightly elevated temperature and then a solution of the nitro compound 7, preferably in one of the abovementioned solvents, is added. Stirring is continued at a constant temperature until the reaction is complete. The reaction mixture is worked up in the usual way. The products are purified by crystallization or by chromatographic methods depending on their crystallization tendencies.
The final reduction of 9 leads to the compounds of formula 6 (corresponding to compounds of formula 1 wherein X denotes O and the groups R5 and R6 denote hydrogen). This reduction is preferably carried out by catalytic hydrogenation, preferably on palladium catalysts or on Raney nickel in alcoholic solvents, preferably in methanol, at ambient temperature. The reaction mixture is worked up in the usual way. The products are purified by crystallization or by chromatographic methods depending on their crystallization tendencies.
The ammonium salts 1-Y are synthesized in the same way as the preparation of compounds 1 starting from the amines 6, using standard methods (Diagram 3). 
Diagram 3
The reaction according to stage (vii) may be carried out, on the one hand, in such a way that tertiary amines of formula 1 wherein neither R5 nor R6 denotes hydrogen, are obtained directly, or by a suitable choice of the reaction conditions may lead to secondary amines of formula 1 wherein either R5 or R6 denotes hydrogen. The latter may then be alkylated, on the one hand, by repeating stage (vii) to obtain tertiary amines, or may be subjected directly to stage (viii), in order to give access to the ammonium salts 1-Y.
In order to carry out the process according to stage (vii) an amine of general formula 6 is dissolved in an organic solvent such as dimethylformamide, dimethylacetamide, methylene chloride, or tetrahydrofuran, preferably dimethylformamide and most preferably anhydrous, optionally absolute dimethylformamide or methylene chloride. The solution thus obtained is combined with an inorganic or organic base and a corresponding alkylating agent. The base used may be an alkali metal- or alkaline earth metal carbonate of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, or calcium carbonate, preferably potassium carbonate. It is also possible to use the hydrogen carbonates of lithium, sodium, and potassium. Moreover, the alkali metal- or alkaline earth metal hydroxides of lithium, sodium, potassium, magnesium, calcium, but preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide in alcohols or water may also be used. It is also possible to use, as further bases, alkoxides of alkali metals and alkaline earth metals, preferably the ethoxides of sodium and potassium. It is also possible to use alkali metal- and alkaline earth metal hydrides, preferably of potassium or sodium, preferably in inert solvents such as dimethylformamide, dimethylacetamide, methylene chloride, ethers, tetrahydrofuran, and toluene. The organic base is preferably an organic amine, most preferably diisopropylethylamine, triethylamine, a cyclic amine such as DBU, or pyridine. The alkylating agents used may be alkyl halides such as alkyl chloride, alkyl bromide, particularly alkyl iodide as well as alkyl tosylates, mesylates, triflates, and dialkylsulfates. The alkyl groups of the alkylating agents correspond to the definitions of R5 and R6 specified hereinbefore. The reaction mixture is stirred for 0.5 to 4 days, preferably 1 to 2 days at ambient temperature and evaporated to dryness. The reaction mixture is worked up in the usual way. The products are purified by crystallization or by chromatographic methods depending on their crystallization tendencies. The method described above for stage (vii) may be used to prepare the ammonium salts 1-Y starting from the amines 1 (stage viii).
Alternatively to the procedure described above the compounds of formula 1 may also be prepared according to stage (vii) by reductive amination of the amines 6 with carbonyl compounds in the presence of a reducing agent. The reaction of the amines 6 with the carbonyl compounds to obtain the Schiff bases formed as intermediates is carried out in solvents such as toluene, dichloromethane, ethyl acetate, ether, tetrahydrofuran etc., preferably at ambient temperature. It may be carried out in the presence of an acid, preferably in the presence of acetic acid. The subsequent reduction may be carried out with complex hydrides such as, for example, LiAlH4, Li-alkoxyhydrides, NaBH4, NaBHCN3, NaBH(OAc)3, etc. NaBH4 is preferably used for the reaction with primary amines, NaBH(OAc)3 for secondary amines. When preparing the methyl compounds by reacting with formalin it is advisable to use formic acid as solvent. The reaction mixture is worked up in the usual way. The products are purified by crystallization or by chromatographic methods depending on their crystallization tendencies.
Alternatively to the procedure described above the compounds of formula 1 may also be prepared by the procedure shown in Diagram 4. 
Diagram 4
Starting from suitably substituted benzoic acids the desired acetophenone intermediates 12 may be obtained by methods known from the literature (Recl. Trav. Chim. Pays-Bas 61, 539-544 (1942)) by Grignard reaction with the corresponding acid chlorides 10 (stage ix). These intermediates 12 are preferably brominated in ether to form the compounds 13 (stage x) and conveniently converted without further purification into the aminoethanol intermediates 15 via the aminoketones 14 and immediate reduction thereof (stage xii), preferably with sodium boranate in isopropanol or with lithium alanate in diethylether or tetrahydrofuran. Optically active aminoethanol intermediates 15 may be obtained stereospecifically by asymmetric hydrogenation using methods known from the literature e.g., with rhodium catalysts using (S,S)- or (R,R)-BCPM (Chem. Pharm. Bull. 43, 738 (1995)).
Etherification to obtain the compounds 1 (wherein X denotes oxygen) with variation of the chain length of A is carried out for example using benzylhalides, preferably using potassium tert-butoxide as auxiliary base (A=C1), by Reppe reaction using optionally substituted phenylacetylenes and subsequent hydrogenation of the resulting Z/E olefins (A=C2) and by Williamson etherification using phenylalkylhalides, preferably using crown ethers (e.g., A is C3). At this point reference should also be made to the general remarks on stage (iii) according to Diagram 1 which are also applicable here.
Starting from the compounds of formula 3 the compounds of general formula 1 wherein X denotes xe2x80x94NHxe2x80x94 may also be obtained by the method shown in Diagram 5. 
Diagram 5
To perform the process according to stage (vii) an amine of general formula 3 is dissolved in an organic solvent such as dimethylformamide, dimethylacetamide, methylene chloride, or tetrahydrofuran, preferably dimethylformamide, and most preferably anhydrous, optionally absolute dimethylformamide or methylene chloride. The solution thus obtained is combined with an inorganic or organic base and a corresponding alkylating agent. The base used may be an alkali metal carbonate or alkaline earth metal carbonate of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, or calcium carbonate, preferably potassium carbonate. It is also possible to use the hydrogen carbonates of lithium, sodium, and potassium. Moreover, the alkali metal hydroxides or alkaline earth metal hydroxides of lithium, sodium, potassium, magnesium, calcium, but preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide in alcohols or water may also be used. It is also possible to use, as further bases, alkoxides of alkali metals and alkaline earth metals, preferably the ethoxides of sodium and potassium. It is also possible to use alkali metal hydrides or alkaline earth metal hydrides, preferably of potassium or sodium, preferably in inert solvents such as dimethylformamide, dimethylacetamide, methylene chloride, ethers, tetrahydrofuran, and toluene. The organic base is preferably an organic amine, most preferably diisopropylethylamine, triethylamine, a cyclic amine such as DBU, or pyridine. The alkylating agents used may be alkyl halides such as alkyl chloride, alkyl bromide, particularly alkyl iodide as well as alkyl tosylates, mesylates, triflates, and dialkylsulfates. The alkyl groups of the alkylating agents correspond to the definitions of R5 and R6 specified hereinbefore. The reaction mixture is stirred for 0.5 to 4 days, preferably 1 to 2 days at ambient temperature and evaporated to dryness. The reaction mixture is worked up in the usual way. The products 16 are purified by crystallization or by chromatographic methods depending on their crystallization tendencies.
The compounds of formula 17 wherein L denotes a leaving group, selected from chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate, or p-toluenesulfonate may be prepared from the compounds of formula 16 by reaction according to stage (xiv). If R5 or R6 equals hydrogen, protecting groups according to the prior art should be used. If L denotes chlorine or bromine, the reaction may be performed using common halogenation reagents. If L denotes methanesulfonate, trifluoromethanesulfonate, or p-toluenesulfonate the compounds 16 may be reacted with the corresponding sulfonic acid chlorides or anhydrides to obtain the compounds 17 in inert solvents such as dimethylformamide, dimethylacetamide, methylene chloride, ethers, tetrahydrofuran, and toluene in the presence of organic amines such as, preferably, diisopropylethylamine, triethylamine, cyclic amines such as DBU, or pyridine.
The compounds of formula 1 wherein X denotes xe2x80x94NHxe2x80x94 may be obtained from the compounds 17 by reacting with the amines 18 under the reaction conditions described hereinbefore for stage (vii). The compounds of formula 1 wherein X denotes xe2x80x94N(C1-C6-alkyl)- or xe2x80x94N(C3-C6-cycloalkyl-C1-C4-alkylene)- may also be obtained therefrom. This reaction is carried out under the reaction conditions described for stage (vii) by alkylation of the compounds of formula 1 wherein X is xe2x80x94NHxe2x80x94 with alkylating reagents C1-C6-alkyl-L or C3-C6-cycloalkyl-C1-C4-alkyl-L, where L may have the meanings given hereinbefore.
Starting from the compounds of formula 1 wherein X is xe2x80x94NHxe2x80x94, the compounds of general formula 1 wherein X denotes xe2x80x94N(CHO)xe2x80x94 or xe2x80x94N(COxe2x80x94C1-C6-alkyl)- may be obtained by the method illustrated in Diagram 6. 
Diagram 6
The reactions according to Diagram 6 may be carried out analogously to formulation and acylation processes which are known per se.